Prospective Phase-II Trial of induction chemotherapy and chemoradiotherapy plus/minus the PD-L1 antibody durvalumab followed by surgery or definitive chemoradiation boost and consolidation durvalumab in resectable stage III NSCLC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Essen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Nov 2019 → ongoing

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Astra Zeneca · Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts

External identifiers

EU CT number

2024-513039-26-00

EudraCT number

2019-000058-77

ClinicalTrials.gov

NCT04202809

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

The primary objective is to assess the efficacy of a multimodality
treatment in resectable stage III non-small-cell lung cancer patients
including a complex induction chemoimmunotherapy followed by a
radiochemoimmunotherapy and definitive surgical resection or
radiochemotherapy-boost and immunotherapy consolidation for 32
weeks versus the same multimodality treatment protocol without
immunotherapy in the induction and radiochemotherapy as measured by
two-year progression-free survival.

Secondary objectives 1

1. The secondary objective is to analyze the toxicity and efficacy of a multimodality treatment in resectable stage III non-small-cell lung cancer patients including a complex induction chemoimmunotherapy followed by a radiochemoimmunotherapy and definitive surgical resection or radiochemotherapy-boost and immunotherapy consolidation for 32 weeks versus the same multimodality treatment protocol without immunotherapy in the induction and radiochemotherapy as measured by response, survival parameters, QoL, compliance and treatment toxicity effects. The secondary objective will be will be achieved by the following secondary endpoints: • To investigate the rate of pathological complete response • To investigate the toxicity and the following surgical resection • To investigate 2-y-overall survival rate • To investigate functional and RECIST response • Progression free survival time • Overall survival • Histopathologic complete response • Other adverse events • Quality of life

Conditions and MedDRA coding

non-small cell lung cancer stages IIIA (N2) and selected resectable stages IIIB

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Body weight >30 kg
2. Age ≥ 18 years and ≤ 75 years
3. Male or female patients. Female (as well as male) patients have to take care of effective measures of anticonception
4. Histologically proven non-small cell lung cancer
5. Selected patients with non-small cell lung cancer stages IIIA and IIIB:  IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy  IIIA: bulky N2-disease histologically proven at EBUS/cervical mediastinoscopy/parasternal mediastinotomy, not diffuse mediastinal involvement  selected IIIB: N3-disease with contralateral mediastinal nodes involved at EBUS/mediastinoscopy  potentially resectable T4-disease: o involvement of the pulmonary artery (angiogr.-CT/MRI/TEE), o involvement of the carina (histologically proven), o involvement of the left atrium (angiogr.-CT/MRI/TEE), o involvement of the vena cava (angiogr.-CT/MRI/TEE), o involvement of ipsilateral intrapulmonary satellite nodules, o mediastinal involvement (not diffuse)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Resectable disease at the time of inclusion
8. Fulfillment of adequate criteria for functional and medical resectability as described in the ERS/ESTS guidelines [Brunelli et al 2009] and acceptable general clinical condition for multimodality treatment (interdisciplinary committee)
9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
10. Must have a life expectancy of > 12 weeks
11. Adequate normal organ and marrow function as defined below: o Haemoglobin ≥ 9.0 g/dL o Absolute neutrophil count (ANC) > 1.5 x 109/L (> 1500 per mm3) o Platelet count ≥ 100 x 109/L (≥ 100.000 per mm3) o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. o AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal o Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24- hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL)
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: o Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) o Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
14. Stable cardiac function (no Myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)

Exclusion criteria 40

1. resectable IIB or selected IIIA (T3N0; T3N1)
2. invasion of spine (T4 – spine)
3. (full blown) Pancoast-syndrome in tumors of the superior sulcus (T3-4 Nx)
4. malignant (positive) pericardial effusion (M1a – pericardial effusion)
5. malignant (positive) pleural effusion (M1a – pleural effusion)
6. involvement of the contralateral hilar nodes (if any data available)
7. endobronchial tumor extension to the contralateral main stem bronchus
8. unresectable disease pre-treatment
9. mixed histology with areas of small cell carcinoma (neuroendocrine markers)
10. clinically symptomatic vena cava superior syndrome
11. diffuse mediastinal involvement
12. patients with T3N3 and T4N3 tumors (IIIC IASLC/UICC 8)
13. invasion of the thoracic aorta (T4 – aorta)
14. invasion of the heart (except left atrium – T4 – heart)
15. invasion of the esophagus (T4 – esophagus)
16. ipsi- or contralateral supraclavicular nodes (N3 – supraclavicular nodes)
17. lung or heart function not allowing at the time of inclusion the intended surgical procedure
18. previous administration of chemotherapy and/or radiotherapy within five years prior to randomization
19. previous immunotherapy within five years prior to randomization
20. insufficient patients compliance (e.g. symptomatic psychiatric disorder)
21. loss of weight > 10 % in the last six months
22. missing written informed consent or definitive refusal for participation
23. Participation in another clinical study with an investigational product during the last 12 months
24. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
25. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
26. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan
27. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
28. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
29. History of allogenic organ transplantation
30. History of a stem cell transplantation
31. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: – Patients with vitiligo or alopecia – Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement – Any chronic skin condition that does not require systemic therapy – Patients without active disease in the last 5 years may be included but only after consultation with the study physician – Patients with celiac disease controlled by diet alone
32. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled diabetes, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
33. History of another primary malignancy except for – Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence – Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease – Adequately treated carcinoma in situ without evidence of disease
34. History of active primary immunodeficiency
35. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV-1 or HIV-2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
36. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: – Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) – Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent – Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
37. Current or prior use of immunostimulatory agents within 14 days before the first dose of durvalumab
38. Receipt of live attenuated vaccine within 90 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP
39. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
40. Known allergy or hypersensitivity to durvalumab or any excipient

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the progression-free survival rate

Secondary endpoints 5

1. Overall survival
2. Occurrence of pulmonary adverse effects of grade > 3 according to CTCAE 5.0.
3. Occurrence of immune therapy related adverse effects of grade > 3 according to CTCAE v.5.0.
4. Adverse events with at least probable relationship to study procedures will counted in total and separate according to CTCAE criteria.
5. Quality of life (QoL C30 and Qol-LC13) date will be analyzed descriptively calculation mean scores, standard deviations median minimum and maximum of the scores.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Essen AöR

Sponsor organisation

Universitaetsklinikum Essen AöR

Address

Hufelandstrasse 55, Holsterhausen Holsterhausen

City

Essen

Postcode

45147

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

PD Dr. med. Wilfried Eberhardt

Public contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Study Coordination

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications